Our goal is to increase understanding of the stromal-epithelial interactions that mediate actions of ovarian steroids in the reproductive tract. Our studies have focused on regulation of two stromally-derived growth factors, hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF), and on regulation of specific enzymes called matrix metalloproteinases (MMPs). First, we have developed a nuclease protection assay for detection of monkey HGF transcript, and determined that the endometrium expresses a long (full length) and a shorter (truncated) form of HGF. Second, we tested the effects of exogenous KGF on the reproductive tract of juvenile and adult rhesus monkeys and found that KGF inhibited endometrial epithelial apoptosis, and blocked atrophy of the spiral arteries after P withdrawal. Third, we have immunocytochemically analyzed the distribution of three key MMPs including, matrilysin (Mat), gelatinase-A (Gel-A), stromelysin-1 (Str-1) and the MMP inhibitor TIMP-1 in the macaque endometrium. This analysis revealed that all three MMPs and TIMP-1 were strongly detectable 2 days after P withdrawal whether E2 was present or not. Gel-A and Str-1 were upregulated in the upper functionalis directly within the zone of fragmentation, while matrilysin was expressed in the glands below the fragmenting zone. Therefore, Gel-A and Str-1 may be more directly involved in stromal fragmentation, while matrilysin probably functions in glandular remodeling. Fourth, we defined the critical period for P withdrawal-induced bleeding by replacing P at various timepoints after P withdrawal at the end of the artificial cycle. Replacement of P before but not after 36 h of P withdrawal blocked frank menses. A critical period' of approximately 36 hours of P withdrawal is needed for key factors such as cytokines and MMPs to rise above a functional threshold that inevitably results in menstrual breakdown. P cannot suppress these factors once that threshold is passed.